PARKINSON'S

Parkinson's is the second most common neurodegenerative disease. It is named after an English physician who first recorded it in with a detailed description in 1817, named James Parkinson.

The risk factors for Parkinson's - Age, Genetic history, Male gender, shyness, depression, any environmental exposure like herbicides, or magnesium and iron exposure, etc.

Classification of Parkinson's - 

1. Classical - Genetic, sporadic, Lewy body with dementia

2. Atypical - Multiple system atrophy, Cerebellar type,  corticobasal ganglionic degeneration, frontotemporal dementia

3. Secondary Parkinson - Drug induced, tumor associated, liver failure, Normal pressure hydrocephalus, toxins like Carbon monoxide poisoning, cyanide poisoning, etc.

How it is caused?

Parkinson is a disease which is mainly involved with the BASAL GANGLIA of the brain.

Basal Ganglia consist of -

Globus pallidus - external and internal

Thalamus

Subthalamic nuclei

Caudate nucleus

Putamen

Substantia nigra

These structures form a direct and indirect pathway that relay connections from the cerebral cortex to and fro to thalamus and other areas of brain that are related in the motor aspect of its functioning

The Neurotransmitter involved in this are - 

Glutamate

GABA

Dopamine

Acetyl Choline

 

The direct pathway goes like this - 

Cerebrum - Caudate nucleus + Putamen (together called as Neostriatum) - Globus pallidus internus - Thalamus - Cerebrum

The neurotransmitter present in between Thalamus and Cerebrum that facilitates the transmission is Glutamate. Where as For Globus Pallidus Internus and Neostriatum is GABA (Gamma Amino Butyric Acid).

Due to this setup, there is stimulatory action and the movements are carried out. Example if you move hand up in the air, for this movement to occur, your brain goes through this pathway.

Also there are collateral branches to Substantia nigra from neostriatum. Where ACh or Acetyl choline acts as a neurotransmitter. Acetyl choline acts as a regulatory neurotransmitter that prevents unwanted stimulation of Substantia nigra as ACh is antagonistic to Dopamine and Melanin.

Inside Substantia nigra, there is Melanin, which acts as a precursor to Dopamine

This Image shows the substantia nigra in the mid brain (from a dissection). Note the changes in the density and intensity of the black pigment melanin which serves as the initial component in dopamine synthesis.

Since, there is decreased Dopamine in the brain, it causes increased ACh and Reduced activity of Indirect pathway leading to increased uncontrolled movements.

These uncontrolled movements are called as parkinsons tremor and clasically seen as rolling movements.

Genetically it appears to be a Double Hit process, where a gene mutation is not capable of causing the disease alone but along with the other factors it manifests the disease.

A mutation in the alpha-synuclein promote misfolding of the proteins forming oligomers that promote cell death. Increased levels of unwanted proteins could also lead to the clearance process where the damaged proteins are failed to be removed from the body.

 This is how an alpha synuclein protein looks like.

Other genes involved with mitochondrial dysfunction are PINK1 and DJ1.

Parkinsons can also be Autosomal Dominant disease if the following chromosomes are involved. - 

Chr 2 

Chr 4 

with the following locus q21-23, p13, q 36-37

It may also be Autosomal Recessive when there is involvement of Chr 1, Chr 12, Chr 22.

X-linked cases are reported to be sporadic in nature.

Clinical Picture -   

Three cardinal things are to be noted - 

Resting tremor

Bradykinesia (Generalised slowing of movements)

Muscle rigidity

These symptoms progress as the disease progress

Resting tremors are Bilateral and present in the Upper limb which worsens with the duration as the disease progresses. 

Tremors occur in the hands, legs, jaw, face, which disappear with purposeful movements

 This video shows the classical Pill Rolling tremors seen in Parkinsonism.

Patients also suffer from - 

Cognitive impairment

Olfactory impairment (smell sensation is altered)

Dysphagia (difficulty in swallowing)

GI dysfunction

Depression

Sleep impairment

Drugs that cause Parkinsonism are - 

Antipsychotics

Metoclopramide

Reserpine

Tetrabenazine

Amphetamines 

Cocaine etc

Treatment of Parkinsonism is medical based and surgical based.

Medically we give any one of the following in combination with others - 

Dopamine agonist - Bromocriptine, Ropinirole 

Dopamine Precursor - Levodopa (L-Dopa)

Peripheral Decarboxylase inhibitor - Carbidopa

MonoAmineOxidase - B (MAO - B) inhibitors - Selegiline, Rasagiline

Anti cholinergics like - Procylidne, Trihexyphenidyl, Biperidine,

The best drug of treatment is Levodopa - Carbidopa Combination

This works best because Levodopa is quickly metabolised in the blood vessels, hence alone is not possible. Thus Carbidopa blocks the peripheral decarboxylase enzyme, preventing the metabolism of Levodopa; which then crosses the Blood-Brain-Barrier (BBB) and enters the brain; thus maintaining the Dopamine levels and replenishing them.

But if any of this is not able to control the disease, we opt for DEEP BRAIN STIMULATION (DBS) surgery.

Where the point of origin is identified by the electro mapping of brain. Then the particular voltage and current is identified at which the pathway is taking place, for example, suppose the pathway works for a voltage of 3mV and current of 5mA is recorded; then the extrenal circuitry is placed deep into the brain with these exact values of functioning. This helps in achieving the normal body movements.

To Access the progress of the patient during surgery, the patient is kept awake and asked to draw spirals on a sheet of paper. The tweaking and modulation to the circuitry is done until the patient draws clean spirals with minimal shakiness. 

This diagram shows the initial spiral drawn by the patient on the sheet with parkinson's

and next spiral which is clean and with minimal distortion indicating the level of precision achieved by the DBS surgery